tbuckley/cabot-search huggingface dataset:
Abstract 6415: CD25-targeted aptamer-drug conjugate (CD25-ApDC) depletes and blocks regulatory T cells selectivel
Authors: Daekyun Lee, Ju-hyung Kang, Inu Song
Journal: Cancer Research (2023)

Abstract Background: Regulatory T cells (Tregs) have a strong immunosuppressive function, inhibit anti-tumor immunity, and promote the occurrence and development of tumors. In addition, a high infiltration of Treg cells is associated with poor survival in various types of cancer. Since CD25 is highly expressed on Treg cells, it is a potential target protein for Treg depletion. Methods: The binding affinity(Kd) of CD25 aptamer to rhCD25 protein was calculated through bio-layer interferometry(BLI). The cell binding of Cy5-labelled CD25 aptamer was detected by flow cytometry, and the internalization was visualized by confocal microscopy. The cell internalization rate was determined using the MFI value of flow cytometry. Competitive ELISA, western blot, and qPCR were performed to investigate the effect of CD25 aptamer on CD25/IL-2 binding. In vitro cytotoxicity of prototype-ApDC was determined by CCK-8 assay. Moreover, CD25-dependent cytotoxicity of prototype-ApDC was evaluated by Karpas299(Treg-like):HuT78(Teff-like) 1:1 co-culture model using FACS analysis. Results: CD25 aptamer binds human CD25 protein with 4.64nM affinity. CD25 aptamer showed selective binding and internalization to CD25-positive Karpas299 and had no interaction with CD25-negative Daudi. The internalization half-time of CD25 aptamer in karpas299 was determined to 9.9 min (95% CI 8.2~12.6min). Interestingly, CD25 aptamer was identified as IL-2R antagonist by evaluating competitive ELISA and the level of phosphor-STAT5 and downstream mRNA expression of TGF-beta. The IC50 value of prototype-ApDC was 24nM to Karpas299 while &amp;gt;1uM to Daudi. These results show that prototype-ApDC has selective cytotoxicity against CD25-expressing cells. Furthermore, in a study of an in vitro co-culture model mimicking the Treg-rich intratumoral T cell environment, prototype-ApDC treatment induced CD25-specific depletion resulting in escalating the ratio of HuT89/Karpas299 with increasing exposure time. Conclusions: Our CD25-targeted aptamer and its drug-conjugated ApDC have demonstrated the selective blocking of IL-2R-STAT5 signaling and induction of CD25-positive cell-specific depletion, respectively. Moreover, in the co-culture system of the Treg-like and Teff-like cells, CD25-ApDC also proved its cytotoxic selectivity. Therefore, one potential strategy in cancer patients is to use CD25-ApDC with excellent tumor permeability as an anticancer agent with a mechanism of Treg cell depletion through specific targeting of CD25 overexpressed in tumor-infiltrating Treg cells. Citation Format: Daekyun Lee, Ju-hyung Kang, Inu Song. CD25-targeted aptamer-drug conjugate (CD25-ApDC) depletes and blocks regulatory T cells selectivel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6415.
Abstract 6498: Association of lifestyle related risk factors with multiple myeloma mortality rates in the United States
Authors: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Himaja Kumari Avvaru, Poornima Ramadas
Journal: Cancer Research (2023)

Abstract Background: The prognosis for multiple myeloma (MM) has significantly improved over the years. Lifestyle risk factor modifications have improved the quality of life in MM patients, however, their effect on the survival outcomes in these patients remains unknown. Methods: We extracted data on age-adjusted mortality rate (AAMR) rates of MM (per 100,000 population) for all 50 U.S. states and the District of Columbia from the Center for Disease Control (CDC) WONDER database (2015-2019). Data on risk factors such as obesity, physical activity, alcohol, tobacco abuse, and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2021). Florida was excluded due to missing information. Correlations were analyzed using Pearson’s coefficient. Statistical analysis was performed using VassarStats. Results: Median AAMR of MM in the US was 3.2 (IQR 2.7, 3.7) per 100,000 population. States with higher age-adjusted prevalence (AAP) percentages of obesity had higher AAMR (r=0.39, p=0.004) of MM. This association was significant in non-Hispanic white (r=0.32, p=0.021), and non-Hispanic black (r=0.31, p=0.034) subgroups as well. States with a higher AAP of adherence to recommended weekly aerobic activity had lower AAMR (r=-0.37, p=0.007). We did not identify any correlation of AAMR with AAP of binge drinking (r=-0.036, p=0.803), consumption of fruits (r=0.04, p=0.75), vegetables (r=-0.133, p=0.357), and smoking history (r=0.052, p=0.72). Conclusions: In the current analysis, a higher prevalence of obesity and lower rates of aerobic physical activity were strongly associated with increased AAMR of MM. Our results, therefore, underscore the need for emphasis on a holistic approach in the management of MM by including lifestyle-based risk factor modification, to further improve the survival outcomes in patients with MM. Citation Format: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Himaja Kumari Avvaru, Poornima Ramadas. Association of lifestyle related risk factors with multiple myeloma mortality rates in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6498.
Abstract 602: Single cell evaluation of intratumoral B cells across solid tumor indications
Authors: Shawn P. Fahl, Kerri Colwell, Casey Smith, Cavin Ott, Alex Moore, Kayla Williams
Journal: Cancer Research (2023)

Abstract The immune system is a critical component of the tumor microenvironment that has both tumor-promoting and tumor-eradicating activity based on the specific immune cell subtype and their activation status. T lymphocytes represent the largest lymphocyte population within the tumor, and numerous immunotherapies have been developed to specifically target this cellular subset. B cells are the next most abundant lymphocyte subset within the tumor microenvironment, and recent studies have identified crucial roles for intratumoral B cells in the production of tumor-reactive antibodies. Using human dissociated tumor cells (DTCs) samples, we have profiled intratumoral B cells to determine their frequency and subset breakdown across thirteen different solid tumor indications. Intratumoral B cells were prevalent in lung cancer and cancers of the gastrointestinal tract (esophageal, gastric, and colorectal), while they were rarer in cancers of the female reproductive tract (endometrial and ovarian). The transcriptional profile and B cell repertoire of the intratumoral B cell subsets were evaluated to provide a deeper understanding of the biology of these tumor-infiltrating lymphocyte subsets. Additionally, spatial transcriptomics were utilized to understand the spatiotemporal location of these subsets within the tumor microenvironment. These studies will provide critical insight for the development of the next generation of immunotherapies. Citation Format: Shawn P. Fahl, Kerri Colwell, Casey Smith, Cavin Ott, Alex Moore, Kayla Williams. Single cell evaluation of intratumoral B cells across solid tumor indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 602.
Abstract 1804: Durable eradication of tumors by single injections of a pHLIP-STING agonist
Authors: Donald M. Engelman, Yana K. Reshetnyak, Oleg A. Andreev
Journal: Cancer Research (2023)

Abstract Purpose: pHLIPs (pH-Low Insertion Peptides) target cell surface acidity resulting from the metabolism of cells in a solid tumor. The acidity causes pHLIPs to insert as transmembrane helices, and attached cargoes can be delivered into targeted cells. STING agonists can trigger an immune response when they are inside cells. pHLIP targeted delivery of a STING agonist (STINGa) effectively triggers cytokine secretion to mobilize the immune system to eradicate tumors while avoiding side effects. Experimental Procedures: Constructs consisting of a pHLIP peptide (Var3) linked to a STINGa (diABZI) via a self-immolating linker were synthesized and characterized. Activation of the STING pathway by the agent was confirmed in cells. Small (100 mm3) and large (400-700 mm3) tumors were grown in female Balb/c mice following flank injections of CT26 colorectal cancer cells. Randomized groups of mice were injected i.p. or i.v. with pHLIP-STINGa made with L- or D- amino acid pHLIP peptides, STINGa alone, pHLIP alone or vehicle. Tumor size and body weight were then measured 3 times per week. The durability of the response to the agent was tested by a second injection of CT26 cells after 60 days. In separate experiments, the identities of targeted immune and stromal cells, the production of cytokines, the PK, tumor targeting and biodistribution were assessed. Results and Conclusions: pHLIP extends the lifetime of a STINGa in the blood 6-fold and delivers STINGa to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs), and dendritic cells (DCs). The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small and large CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the TME pH increased, which is important for the efficient cytotoxic activity of immune cells. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice lacking T-cells. Inhibition of MHC-I negative B16F10 melanoma tumor growth was also observed in Balb/c mice. Thus, targeted delivery of the STINGa to the tumor stroma and TAMs activates signaling, potentially resulting in the recruitment and infiltration of both T-cells and NK-cells, which gain access to the tumor core. The cytotoxic activity of immune cells is enhanced, and immune memory is developed. Citation Format: Donald M. Engelman, Yana K. Reshetnyak, Oleg A. Andreev. Durable eradication of tumors by single injections of a pHLIP-STING agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1804.
Abstract 6423: Targeting an autophagy regulator augments antitumor immunity and immunotherapy
Authors: Yi Bao, Yuanyuan Qiao, Arul Chinnaiyan
Journal: Cancer Research (2023)

Abstract Immunotherapy has strikingly changed the landscape of cancer treatment, yet many patients fail to respond to the therapy exhibiting primary resistance. Accumulating evidence has supported that autophagy inhibition may sensitize tumor to immunotherapy. Here, we found that pharmaceutical or genetic inhibition of an autophagy regulator induces MHC class I surface expression in cancer cells. In a co-culture of OT1 CD8+ T cells and ovalbumin-expressing cancer cells, inhibition of the regulator enhances CD8+ T cell killing and increases functional and proliferative CD8+ T cells. Concordantly, genetic depletion or inhibition of the regulator elevates MHC class I in tumor cells, reduces tumor growth, and increases intratumoral functional CD8+ T cells in syngeneic mouse models. Furthermore, we found that inhibition of the regulator sensitizes syngeneic tumors to anti-PD1 therapy. Collectively, inhibition of this autophagy regulator augments antitumor immunity and immunotherapy via inducing MHC class I surface expression in cancer cells. Citation Format: Yi Bao, Yuanyuan Qiao, Arul Chinnaiyan. Targeting an autophagy regulator augments antitumor immunity and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6423.
Abstract 6005: Promoter methylation occurs at high frequencies regardless of mutation status of tumor-associated genes in oral malignancies
Authors: Masanobu Abe, Kazuto Hoshi, Toshikazu Ushijima
Journal: Cancer Research (2023)

Abstract Background: Genetic and epigenetic alterations are both important in tumorigenesis. However, their association in oral carcinogenesis has not been fully investigated yet. In this study, we analyzed somatic mutations of tumor-related genes and promoter methylation of tumor-suppressor genes (TSGs) in oral malignancies/premalignancies, and analyzed their association. Materials and Methods: 39 oral squamous cell carcinomas (OSCCs) and 2 oral epithelial dysplasias (OEDs) were obtained as fresh-frozen?. Somatic mutations of 46 tumor-related genes, 13 TSGs and 33 oncogenes, were analyzed by targeted next-generation sequencing (NGS). Promoter methylation of five TSG: (p16/INK4A, CMTM3, EGFLAM, NKX2-3, and RBP4) were determined by methylation-specific PCR (MSP). Results: Somatic mutations of tumor-related genes were observed in 63.4% of 41 OSCCs/OEDs. Particularly, mutations of p53 and PIK3CA were observed 39.0% and 31.7%, respectively, of the 41 OSCCs/OEDs. Promoter methylation of p16/INK4A, CMTM3, NKX2-3, RBP4, and EGFLAM were observed in 34.1%, 48.8%, 41.5%, 68.3%, and 36.6%, respectively, of the 41 OSCCs/OEDs. No differences in the frequency of promoter methylation of the five genes were observed between tumors with and without somatic mutations of p53 and PIK3CA. Conclusions: Promoter methylation was observed at high frequencies regardless of mutation status of p53 and PIK3CA in OSCCs/OEDs. Oral tumorigenesis appears to be difficult to be explained solely by genetic events indicating involvement of epigenetic events. Citation Format: Masanobu Abe, Kazuto Hoshi, Toshikazu Ushijima. Promoter methylation occurs at high frequencies regardless of mutation status of tumor-associated genes in oral malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6005.
Abstract 2969: Development of a canine PD-L1 antibody and caninized PD-L1 mouse model: an essential translational research tool to raise the success rate of immunotherapy in humans
Authors: Wonkyung Oh, Alyssa Kim, Deepika Dhawan, Perry M. Kirkham, Deborah W. Knapp, Seung-Oe Lim
Journal: Cancer Research (2023)

Abstract Immune checkpoint blockade therapy, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of immune checkpoint blockade therapy, the response rates in cancer patients are limited (~20-40%). To improve immune checkpoint blockade therapy, relevant preclinical animal models are an essential component in the development and testing of multiple combination approaches and strategies. Companion dogs naturally develop several types of cancer that in many respects resemble clinical cancer in human patients. Therefore, the canine studies of immuno-oncology drugs are convertible into knowledge that informs and prioritizes new immuno-oncology therapy in humans. The challenge has been, however, that immunotherapeutic antibodies that target canine immune checkpoint molecules, such as canine PD-L1, have not been commercially available. Here, we developed a new canine PD-L1 antibody as an immuno-oncology drug and characterized its functional and biological properties by multiple assays. Furthermore, the therapeutic efficacy of cPD-L1 antibodies was evaluated in our unique caninized PD-L1 mice. Altogether, these in vitro and in vivo data including an initial safety profile in laboratory dogs, support the development of our canine PD-L1 antibody as an immune checkpoint inhibitor for studies in dogs with naturally occurring cancer for translational research. In conclusion, our new therapeutic antibody and caninized PD-L1 mouse model will be an essential translational research tool in raising the success rate of immunotherapy in both dogs and humans. Citation Format: Wonkyung Oh, Alyssa Kim, Deepika Dhawan, Perry M. Kirkham, Deborah W. Knapp, Seung-Oe Lim. Development of a canine PD-L1 antibody and caninized PD-L1 mouse model: an essential translational research tool to raise the success rate of immunotherapy in humans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2969.
Abstract 4482: Discovery of GH2616, a potent and selective KIF18A inhibitor with robust <i>in vivo</i> efficacy in p53 mutant cancer
Authors: Jie Jack Li, Guiping Zhang, Jiapeng Li
Journal: Cancer Research (2023)

Abstract Chromosomal instability (CIN) is one of the hallmarks of cancer. Cancer cells often undergo whole-genome doubling (WGD) and P53 represents a major barrier to the proliferation of WGD+ cells. Therefore, cancer cells with either CIN or WGD often harbor the p53 mutation. Recently, KIF18A has emerged as a potential therapeutic target in CIN or WGD cancer cells. We have identified a potent and selective KIF18A inhibitor, GH2616. In vitro, GH2616 inhibited the kinesin motor activity with an IC50 less than 50 nM, and with an EC50 less than 50 nM in the mitotic index assay using HT29 cells (WGD). In vivo, GH2616 inhibited the growth of WGD CDX models with a dose dependent manner. GH2616 has good oral bioavailability in different species and metabolic stability for QD dosing. This compound also showed low potential of DDI thus suitable for drug combinations. In a cell panel with more than 200 cell lines, GH2616 selectively inhibit the growth of cells with p53 mutant and some other specific biomarkers in multiple tumor types. In conclusion, we discovered GH2616 as a novel KIF18A inhibitor with potent in vivo efficacy. It is currently under evaluation in IND-enabling studies and IND filing is expected in Q4, 2023. Citation Format: Jie Jack Li, Guiping Zhang, Jiapeng Li. Discovery of GH2616, a potent and selective KIF18A inhibitor with robust in vivo efficacy in p53 mutant cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4482.
Abstract 1017: A novel blood diagnostic method for fibrolamellar hepatocellular carcinoma
Authors: Ruisi Wang, Arlene M. Hurley, Sanford M. Simon
Journal: Cancer Research (2023)

Abstract Fibrolamellar hepatocellular carcinoma (FLC) is an often-lethal liver cancer affecting primarily children and young adults. The disease presents with vague symptoms, and, as a result, it is usually diagnosed at an advanced stage. Thus, there is a high recurrence rate among those who undergo surgical resection. Diagnostic tests based on scans are differentially interpreted by pathologists and radiological, and scans often miss small tumors. We are developing tests for FLC based on metabolites and nucleic acids in the blood and in the urine. We used samples from 29 FLC patients and 9 age/gender-matched healthy donors. A clinical testing lab was used to quantify the plasma for Vitamin B12, alpha-fetoprotein (AFP), estrogen (E2), and liver panel (albumin, alkaline phosphatase, alanine transaminase, aspartate transferase, creatine kinase, direct bilirubin, total bilirubin, total protein, globulin). We found no difference between FLC vs. non-FLC subjects in the liver panel tests. In addition, there is no difference between the AFP and E2 tests. Vitamin B12 levels were about 8.5 times higher (p&amp;lt;0.05) in FLC patients compared to healthy donors. We are currently validating other protein and metabolite markers in the blood and urine, and C-reactive protein in blood and orotic acid in urine. In nucleic acid assays, we found specific miRNAs increased in the circulation. These included: miR-122-5p, miR-514a-5p, miR-192-5p, miR-615-5p, miR-4532, miR-4322, miR-214-3p, and miR-122-3p. They were upregulated 8- to 21-fold in FLC (n= 24) vs. non-FLC patients (n=16). These results identified biomarkers and microRNAs associated with FLC tumors. The tests are currently being evaluated as part of a larger study to determine whether they can detect recurrence of disease and help assess therapeutic responses in FLC patients. Citation Format: Ruisi Wang, Arlene M. Hurley, Sanford M. Simon. A novel blood diagnostic method for fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1017.